Human intrinsic immunity factor SLFN11 promotes cell death upon DNA damages through cleavage of distinct type II tRNAs and inhibition of proteins syntheses related to DNA damage responses and repairs

Abstract

Abstract Previously we showed that as an intrinsic immunity factor, human SLFN11 inhibits HIV viral proteins syntheses by modulating tRNAs abundances and exploiting the biased codon usage of the virus. Transcriptome analysis in vast collection of cancer cell lines revealed that SLFN11 is the only gene whose expression significantly sensitizes tumor cells to DNA damaging agents (DDAs). We hereby report that SLFN11 preferentially inhibits translation of genes involved in DNA damage response and repair, including ATR and ATM, upon DDAs treatment based on their distinct codon usages without disrupting early DNA damage response signaling. Type II tRNAs, which include all serine and leucine tRNAs, are cleaved in a SLFN11-dependent manner in response to DDAs. Genes with high TTA (Leu) codon usage such as ATR display utmost susceptibility to translational suppression by SLFN11 due to the extreme low abundance of cognate tRNA-Leu-TAA. Specific attenuation of tRNA-Leu-TAA with antisense oligonucleotides (ASO) sufficed to ablate ATR protein expression and restore DDA sensitivity of SLFN11-deficient tumor cells. Our study uncovered a novel mechanism of DNA damage response regulation mediated by SLFN11-dependent tRNA cleavage and codon-specific translational inhibition. The immunomodulation of SLFN11 expression and activation can be a potent novel approach to overcome the wide-spreading resistance of tumor cells to chemo-/radio-therapies.